OGG1 inhibition triggers synthetic lethality and enhances the effect of PARP inhibitor olaparib in BRCA1-deficient TNBC cells

Background: PARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types. Methods: We hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478. Results: Knocking out BRCA1 in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of BRCA1 deficiency, reflecting an additive interaction. Discussion: These results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in BRCA1-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer

Calibration of Moisture Sensing with Subsurface Heated Fiber Optics using Numerical Simulation

The heat pulse probe method can be implemented with actively heated fiber optics (AHFO) to obtain distributed measurements of soil water content (θ) by using reported soil thermal responses measured by Distributed Temperature Sensing (DTS) and with a soil-specific calibration relationship. However, most reported applications have been calibrated to homogeneous soils in a laboratory, while inexpensive efficient in situ calibration procedures useful in heterogeneous soils are lacking. Here we employed the Hydrus 2-D/3-D code to define a soil-specific calibration curve. We define a 2-D geometry of the fiber optic cable and the surrounding soil media, and simulate heat pulses to capture the soil thermal response at different soil water contents. The model was validated in an irrigated field using DTS data from two locations along the FO deployment in which reference moisture sensors were installed. Results indicate that θ was measured with the model-based calibration with accuracy better than 0.022 m3 m−3

Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1

: Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with the abasic site (AP site) base excision repair (BER) intermediate. Cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair for 8-oxoguanine DNA glycosylase 1 (OGG1). The OGG1 AP lyase activity can be increased using small molecule binders, called organocatalytic switches, to cleave the DNA backbone in a similar manner as a bifunctional DNA glycosylase. In search for novel organocatalytic switches we here identify 8-Substituted 6 thioguanines and 6-amino-pyrazolo-[3,4-d]-pyrimidine derivatives as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by β-elimination, shaping a complete, artificial AP-lyase function. These new tool compounds enhance the cellular repair of 8-oxoG and AP sites, activating a rudimentary but canonical enzymatic activity

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment